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Germline determinants of the somatic mutation landscape in 2,642 cancer genomes

By Sebastian M. Waszak, Grace Tiao, Bin Zhu, Tobias Rausch, Francesc Muyas, Bernardo Rodríguez-Martín, Raquel Rabionet, Sergei Yakneen, Georgia Escaramis, Yilong Li, Natalie Saini, Steven A. Roberts, German M. Demidov, Esa Pitkänen, Olivier Delaneau, Jose Maria Heredia-Genestar, Joachim Weischenfeldt, Suyash S. Shringarpure, Jieming Chen, Hidewaki Nakagawa, Ludmil B. Alexandrov, Oliver Drechsel, L. Jonathan Dursi, Ayellet V. Segre, Erik Garrison, Serap Erkek, Nina Habermann, Lara Urban, Ekta Khurana, Andy Cafferkey, Shuto Hayashi, Seiya Imoto, Lauri A. Aaltonen, Eva G. Alvarez, Adrian Baez-Ortega, Matthew Bailey, Mattia Bosio, Alicia L. Bruzos, Ivo Buchhalter, Carlos D. Bustamante, Claudia Calabrese, Anthony DiBiase, Mark Gerstein, Aliaksei Z. Holik, Xing Hua, Kuan-lin Huang, Ivica Letunic, Leszek J. Klimczak, Roelof Koster, Sushant Kumar, Mike McLellan, Jay Mashl, Lisa Mirabello, Steven Newhouse, Aparna Prasad, Gunnar Rätsch, Matthias Schlesner, Roland Schwarz, Pramod Sharma, Tal Shmaya, Nikos Sidiropoulos, Lei Song, Hana Susak, Tomas Tanskanen, Marta Tojo, David C Wedge, Mark Wright, Ying Wu, Kai Ye, Venkata D. Yellapantula, Jorge Zamora, Atul J Butte, Gad Getz, Jared Simpson, Li Ding, Tomas Marques-Bonet, Arcadi Navarro, Alvis Brazma, Peter Campbell, Stephen J. Chanock, Nilanjan Chatterjee, Oliver Stegle, Reiner Siebert, Stephan Ossowski, Chun Chieh Fan, Dmitry A Gordenin, Jose M.C. Tubio, Francisco M. De La Vega, Douglas F. Easton, Xavier Estivill, Jan Korbel, on behalf of the PCAWG Germline Working group%, and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network

Posted 01 Nov 2017
bioRxiv DOI: 10.1101/208330 (published DOI: 10.1038/s41586-020-1969-6)

Cancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million germline single nucleotide variants, short insertions/deletions, and large structural variants in whole genomes from 2,642 cancer patients, and employed this genomic resource to study genetic determinants of somatic mutagenesis across 39 cancer types. Our analyses implicate damaging germline variants in a variety of cancer predisposition and DNA damage response genes with specific somatic mutation patterns. Mutations in the MBD4 DNA glycosylase gene showed association with elevated C>T mutagenesis at CpG dinucleotides, a ubiquitous mutational process acting across tissues. Analysis of somatic structural variation exposed complex rearrangement patterns, involving cycles of templated insertions and tandem duplications, in BRCA1-deficient tumours. Genome-wide association analysis implicated common genetic variation at the APOBEC3 gene cluster with reduced basal levels of somatic mutagenesis attributable to APOBEC cytidine deaminases across cancer types. We further inferred over a hundred polymorphic L1/LINE elements with somatic retrotransposition activity in cancer. Our study highlights the major impact of rare and common germline variants on mutational landscapes in cancer.

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